Evaluasi Pelaksanaan RANHAM 2004-2009 dan Rencana Ratifikasi Optional Protocol To The Convention Against Torture (CAT) dalam RANHAM 2004-2009 dan Perencanaan RANHAM 2010-2014

Dalam rangka mengevaluasi kepatuhan (comply) Pemerintah Indonesia dalam menjalankan United Nations Convention Against Torture and Other Cruel, Inhuman or Degrading Treatment or Punishment (UNCAT) yang telah dirati kasi dengan UU No 5 1998, Kemitraan merasa perlu mengadakan kajian ini karena alasan-alasan berikut: (i) Secara hukum Indonesia wajib menjalankan UNCAT karena telah mengikatkan diri pada Konvensi tersebut sejak tahun 1998, sehingga semua pasal-pasal UNCAT (kecuali pasal 20 karena Indonesia mengecualikan diri) bersifat wajib atau legally binding untuk melaksanakannya. (ii) Indonesia belum sepenuhnya mengintegrasikan UNCAT dalam sejumlah peraturan Perundang-undangan nasional sehingga perlu dicermati secara khusus. (iii) Rencana Aksi Nasional Hak Asasi Manusia (RANHAM) 1998-2003 dan RANHAM 2004-2009 dirasa masih memiliki kekosongan substansi dan pelaksanaannya belum konsisten dengan apa yang dituangkan dalam ke dua RANHAM tersebut. Berdasarkan alan-alasan di atas dan makin maraknya pelanggaran HAM yang terjadi di Indonesia, Kemitraan dengan bantuan dana dari Uni Eropa mencoba mengevaluasi secara komprehensive pelaksanaan RANHAM 2004-2009 dan melihat kemungkinan rencana rati kasi Optional Protocol UNCAT yang telah disepakati oleh Majelis Umum PBB pada tanggal 18 Desember 2002 dan telah enter into force pada tanggal 22 Juni 2006. Disamping itu, kajian ini juga memberikan masukan bagi Perencanaan RANHAM 2010-2014

KDM5 inhibition offers a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas

Loss-of-function mutations in KMT2D are a striking feature of the germinal centre (GC) lymphomas, resulting in decreased H3K4-methylation and altered gene expression. We hypothesised that inhibition of the KDM5 family, which demethylates H3K4me3/me2, would re-establish H3K4-methylation and restore the expression of genes repressed upon loss of KMT2D. KDM5-inhibition increased H3K4me3 levels and caused an anti-proliferative response in vitro, which was markedly greater in both endogenous and CRISPR-edited KMT2D mutant DLBCL cell lines, while tumour growth was inhibited in KMT2D mutant xenografts in vivo. KDM5-inhibition reactivated both KMT2D-dependent and -independent genes, resulting in diminished B-cell signalling and altered expression of BCL2 family members, including BCL2 itself. KDM5-inhibition may offer an effective therapeutic strategy for ameliorating KMT2D loss-of-function mutations in GC-lymphomas

Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma

Follicular lymphoma is an incurable malignancy, with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome sequencing on 10 follicular lymphoma-transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy. © 2014 Nature America, Inc.This study was predominantly funded by Cancer Research UK through the Genomic Initiative and Programme grant (15968) to J.F. and was also supported by Leukemia and Lymphoma Research (grant to J.F.) and Hungarian Scientific Research Fund (Országos Tudományos Kutatási Alapprogramok, OTKA) grant K-76204 (to A.M.). Y.F. is a recipient of the Georgia Cancer Coalition Distinguished Scholar Award, and C.P. and Y.F. are, in part, supported by US National Institutes of Health grant GM085261 (to Y.F.). C.B. is a recipient of the European Hematology Association (EHA) Partner fellowship (2009/1) and was supported by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of TÁMOP 4.2.4. A/1-11-1-2012-0001 National Excellence Program. J.O. is a recipient of the Kay Kendall Leukaemia Fund (KKLF) Junior Clinical Research Fellowship (KKL 557)

Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma

Follicular lymphoma is an incurable B cell malignancy characterized by the t(14;18) translocation and mutations affecting the epigenome. Although frequent gene mutations in key signaling pathways, including JAK-STAT, NOTCH and NF-?B, have also been defined, the spectrum of these mutations typically overlaps with that in the closely related diffuse large B cell lymphoma (DLBCL). Using a combination of discovery exome and extended targeted sequencing, we identified recurrent somatic mutations in RRAGC uniquely enriched in patients with follicular lymphoma (17%). More than half of the mutations preferentially co-occurred with mutations in ATP6V1B2 and ATP6AP1, which encode components of the vacuolar H(+)-ATP ATPase (V-ATPase) known to be necessary for amino acid-induced activation of mTORC1. The RagC variants increased raptor binding while rendering mTORC1 signaling resistant to amino acid deprivation. The activating nature of the RRAGC mutations, their existence in the dominant clone and their stability during disease progression support their potential as an excellent candidate for therapeutic targeting